Improved Pulse Wave Velocity and Renal Function in Individualized Calcineurin Inhibitor Treatment by Immunomonitoring

Sommerer, Claudia; Brocke, Janina; Brückner, Thomas; Schaier, Matthias; Morath, Christian; Meuer, Stefan; Zeier, Martin; Giese, Thomas

doi:10.1097/tp.0000000000001973

Cited by 7 publications

(6 citation statements)

References 36 publications

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“…41 NFAT-RGE proved efficacy and safety in individualizing CsA treatment as a translational immune monitoring tool that can reduce cardiovascular risk and improve long-term renal allograft function. 42 This pharmacodynamic analysis supports the identification of patients at risk of side effects and overimmunosuppression and might serve as a reliable assay to lower CNI dosing. In a previous observational single-centre study, NFAT-RGE was low in stable renal allograft recipients with CMV infections.…”

Section: Discussionsupporting

confidence: 52%

“…The feasibility of individualised CNI immunosuppression by pharmacodynamic monitoring was assessed in the prospective randomized Calcineurin‐Inhibitor Sparing trial, and the opportunity to reduce cardiovascular risk and other CNI‐induced adverse events were evaluated 41 . NFAT‐RGE proved efficacy and safety in individualizing CsA treatment as a translational immune monitoring tool that can reduce cardiovascular risk and improve long‐term renal allograft function 42 …”

Section: Discussionmentioning

confidence: 99%

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Monitoring of gene expression in tacrolimus‐treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study

Sommerer

Brunet

Budde

et al. 2021

Brit J Clinical Pharma

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Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy. NFAT-regulated gene expression (RGE) was evaluated in renal allograft recipients as predictive biomarker to detect patients at risk of acute rejection or infections.Methods: NFAT-RGE (interleukin-2, interferon-γ, granular-macrophage colonystimulating factor) was evaluated by quantitative real-time polymerase chain reaction in whole blood samples at day 7, day 14, month 1, 3, and 6 after transplantation in 64 de novo renal allograft recipients from 3 European centres. Immunosuppression consisted of tacrolimus (Tac), mycophenolic acid, and corticosteroids.Results: Tac concentrations (C0 and C1.5) correlated inversely with NFAT-RGE (P < .01). NFAT-RGE showed a high interindividual variability (1-61%). Patients with high residual gene expression (NFAT-RGE ≥30%) were at the increased risk of acute rejection in the following months (35 vs. 5%, P = .02), whereas patients with low residual gene expression (NFAT-RGE <30%) showed a higher incidence of viral complications, especially cytomegalovirus and BK virus replication (52.5 vs.10%, P = .01).Conclusions: NFAT-RGE was confirmed as a potential noninvasive early predictive biomarker in the immediate post-transplant period to detect patients at risk of acute rejection and infectious complications in Tac-treated renal allograft recipients.Monitoring of NFAT-RGE may provide additional useful information for physicians to achieve individualized Tac treatment.The authors confirm that Claudia Sommerer is the principal investigator for this paper and that she had direct clinical responsibility for patients.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Monitoring of gene expression in tacrolimus‐treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study

Sommerer

Brunet

Budde

et al. 2021

Brit J Clinical Pharma

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“…These have the potential to identify patients with overimmunosuppression or with underimmunosuppression, despite apparently normal CNI concentrations, and may further improve therapy. 6,7…”

Section: Introductionmentioning

confidence: 99%

“…20 RGE tmax has been used to guide CNI dosing in kidney transplant patients during clinical trials. 7,21…”

Section: Introductionmentioning

confidence: 99%

“…These have the potential to identify patients with overimmunosuppression or with underimmunosuppression, despite apparently normal CNI concentrations, and may further improve therapy. 6,7 A promising method for measuring CNI effects is the quantification of nuclear factor of activated T-cell-regulated gene expression (NFAT-RGE) using an ex vivo stimulation of full-blood samples. [8][9][10][11] The current application of the NFAT-RGE method is largely based on relative changes in NFAT-RGE 2 hours (ciclosporin) or 1.5 hours (tacrolimus) after oral drug administration, that is, residual NFAT-RGE at the times where maximum concentrations are expected (RGE tmax ).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell–Regulated Gene Expression in Healthy Volunteers

Djaelani

Giese

Sommerer

et al. 2023

Therapeutic Drug Monitoring

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Background: Although therapeutic drug monitoring of calcineurin inhibitor (CNI) concentrations is performed routinely in clinical practice, an identical concentration may lead to different effects in different patients. Although the quantification of nuclear factor of activated T-cell-regulated gene expression (NFAT-RGE) is a promising method for measuring individual CNI effects, CNI pharmacodynamics are as of yet incompletely understood.Methods: CNI concentrations and NFAT-RGEs were quantified in 24 healthy volunteers receiving either ciclosporin or tacrolimus in 2 clinical trials. NFAT-RGE was measured using quantitative reverse transcription polymerase chain reaction tests of whole-blood samples. Pharmacokinetics and pharmacodynamics were analyzed using compartmental modeling and simulation. In addition, NFAT-RGE data from renal transplant patients were analyzed. Results:The average NFAT-RGE during a dose interval was reduced to approximately 50% with ciclosporin, considering circadian changes. The different effect-time course with ciclosporin and tacrolimus could be explained by differences in potency (IC 50 204 6 41 versus 15.1 6 3.2 mcg/L, P , 0.001) and pharmacokinetics. Residual NFAT-RGE at the time of maximum concentration (RGE tmax ) of 15% when using ciclosporin and of 30% when using tacrolimus was associated with similar average NFAT-RGEs during a dose interval. Renal transplant patients had similar but slightly stronger effects compared with healthy volunteers.Conclusions: Ciclosporin and tacrolimus led to similar average suppression of NFAT-RGE in a dose interval, despite considerably different RGE tmax . Pharmacodynamic monitoring of average NFAT-RGE should be considered. When using NFAT-RGE at specific time points, the different effect-time courses and circadian changes of NFAT-RGEs should be considered.

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Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection

Leino

Pai

2020

Clin Pharmacokinet

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Improved Pulse Wave Velocity and Renal Function in Individualized Calcineurin Inhibitor Treatment by Immunomonitoring

Abstract: NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.

Cited by 7 publications

References 36 publications

Monitoring of gene expression in tacrolimus‐treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study

Monitoring of gene expression in tacrolimus‐treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study

Pharmacodynamic Monitoring of Ciclosporin and Tacrolimus: Insights From Nuclear Factor of Activated T-Cell–Regulated Gene Expression in Healthy Volunteers

Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection

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